Due to the increased lifespan of our population, problems linked to age-associated disabilities are becoming more and more important and absorbing a growing portion of the costs associated with healthcare. Since dementia is one of the most common health problem in the elderly, its related cost is projected to be among the highest and predicted to become the leading expense in the next decade. Aging is the strongest risk factor for Alzheimer?s disease (AD), the most common form of dementia characterized by a complex pathogenesis for which in recent years unifying mechanisms have been sought. Loss of protein homeostasis is one common feature to most aging organisms, and growing evidence indicates that disturbances in the systems responsible for protein trafficking (i.e., retromer complex) may contribute to neurodegeneration in the AD brain by interfering with the removal of AD-related pathogenic proteins. Several lines of evidence have implicated dysfunction of the retromer complex in AD including data from human studies, transgenic mouse model of the disease and in vitro models. Among the potential links between the retromer system and the disease emerging evidence showed an involvement in amyloidogenesis. By contrast, no studies have addressed the possibility that this system plays a functional role in the development of tau pathology, the second most common feature of the AD brain. The general hypothesis of this proposal is that functional characterization of the biochemical and biological role of retromer complex will help us to dissect important new aspects of the neuropathology and cognitive decline that characterize AD. In particular, we hypothesize that 1) retromer dysfunction is an early event in the disease pathogenesis 2) preventing its decline will be neuroprotective and that 3) restoration of its function is an effective intervention against AD-related neurodegenerative functional and pathological phenotype. To test these hypotheses, we will use: a clinical model (post-mortem brain tissues), as well as a translational mouse model (transgenic mice). Successful accomplishment of our proposed research program will provide new insights into the neurobiology of the retromer complex system and explore the potential for translating our findings into novel and viable therapeutic opportunities for AD pathology, neurodegeneration and cognitive decline.